An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

In adults, sigmoidoscopy screening invitation reduced CRC incidence and related mortality at 15 y.

SOURCE CITATION: Juul FE, Cross AJ, Schoen RE, et al. 15-year benefits of sigmoidoscopy screening on colorectal cancer incidence and mortality: a pooled analysis of randomized trials. Ann Intern Med. 2022;175:1525-33. 36215714.

In adults, a single colonoscopy screening invitation vs. no invitation reduced CRC incidence at 10 y.

SOURCE CITATION: Bretthauer M, Løberg M, Wieszczy P, et al. Effect of colonoscopy screening on risks of colorectal cancer and related death. N Engl J Med. 2022;387:1547-56. 36214590.

Counting Advanced Precancerous Lesions as True Positives When Determining Colorectal Cancer Screening Test Specificity.

The landmark Centers for Medicare & Medicaid Services (CMS) decision memo on blood-based biomarkers to screen for colorectal cancer (CRC) sets thresholds of 74% or higher for sensitivity and 90% or higher for specificity for CRC. This approach does not consider detection of advanced precancerous lesions as true positives. We contrasted the impact of counting advanced precancerous lesions as true vs false positives and projected CRC outcomes under contrasting tests in a validated model. A test with the threshold performance set by CMS decreased CRC incidence by 30% and CRC mortality by 48% in individuals aged 45 years. If this test also detected advanced precancerous lesions with 30% sensitivity, CRC incidence decreased by 45% and mortality by 58%, but the CRC specificity of the test of only 88% would not satisfy the CMS threshold. CMS should reconsider its definition of threshold specificity for CRC screening biomarkers. Future coverage determinations on biomarkers to screen for cancer should consider detection of relevant precursor lesions and projected outcomes.

New scoring systems for predicting advanced proximal neoplasia in asymptomatic adults with or without knowing distal colorectal findings: a prospective, cross-sectional study.

BACKGROUND: Models estimating risk for advanced proximal colorectal neoplasia (APN) may be used to select colorectal cancer (CRC) screening test, either prior to knowing distal colorectal findings or afterward. Current models have only fair discrimination and nearly all require knowing distal findings. OBJECTIVE: Derive and test risk prediction models for APN with and without distal findings. SETTING: Selected endoscopy centers within central Indiana, USA. PARTICIPANTS: Average-risk persons undergoing first-time screening colonoscopy. INTERVENTIONS: Demographics, personal and family medical history, lifestyle factors and physical measures were linked to the most advanced finding in proximal and distal colorectal segments. For both models, logistic regression identified factors independently associated with APN on a derivation set. Based on equation coefficients, points were assigned to each factor, and risk for APN was examined for each score. Scores with comparable risks were collapsed into risk categories. Both models and their scoring systems were tested on the validation set. MAIN OUTCOME: APN, defined as any adenoma or sessile serrated lesion ≥1 cm, one with villous histology or high-grade dysplasia, or CRC proximal to the descending colon. RESULTS: Among 3025 subjects in the derivation set (mean age 57.3 ± 6.5 years; 52% women), APN prevalence was 4.5%; 2859 (94.5%) had complete data on risk factors. Independently associated with APN were age, sex, cigarette smoking, cohabitation status, metabolic syndrome, non-steroidal anti-inflammatory drug use and physical activity. This model (without distal findings) was well-calibrated (P = 0.62) and had good discrimination (c-statistic = 0.73). In low-, intermediate- and high-risk groups that comprised 21, 58 and 21% of the sample, respectively, APN risks were 1.47% (95% CI, 0.67-2.77%), 3.09% (CI, 2.31-4.04%) and 11.6% (CI, 9.10-14.4%), respectively (P < 0.0001), with no proximal CRCs in the low-risk group and 2 in the intermediate-risk group. When tested in the validation set of 1455, the model retained good metrics (calibration P = 0.85; c-statistic = 0.83), with APN risks in low- (22%), intermediate- (56%) and high-risk (22%) subgroups of 0.62% (CI, 0.08-2.23%) 2.20% (CI, 1.31-3.46%) and 13.0% (CI, 9.50-17.2%), respectively (P < 0.0001). There were no proximal CRCs in the low-risk group, and two in the intermediate-risk group. The model with distal findings performed comparably, with validation set metrics of 0.18 for calibration, 0.76 for discrimination and APN risk (% sample) in low-, intermediate-, and high-risk groups of 1.1 (69%), 8.3 (22%) and 22.3% (9%). CONCLUSION: These models stratify large proportions of average-risk persons into clinically meaningful risk groups, and could improve screening efficiency, particularly for noncolonoscopy-based programs.

Derivation and validation of a predictive model for advanced colorectal neoplasia in asymptomatic adults.

OBJECTIVE: Knowing risk for advanced colorectal neoplasia (AN) could help patients and providers choose among screening tests, improving screening efficiency and uptake. We created a risk prediction model for AN to help decide which test might be preferred, a use not considered for existing models. DESIGN: Average-risk 50-to-80-year olds undergoing first-time screening colonoscopy were recruited from endoscopy units in Indiana. We measured sociodemographic and physical features, medical and family history and lifestyle factors and linked these to the most advanced finding. We derived a risk equation on two-thirds of the sample and assigned points to each variable to create a risk score. Scores with comparable risks were collapsed into risk categories. The model and score were tested on the remaining sample. RESULTS: Among 3025 subjects in the derivation set (mean age 57.3 (6.5) years; 52% women), AN prevalence was 9.4%. The 13-variable model (c-statistic=0.77) produced three risk groups with AN risks of 1.5% (95% CI 0.72% to 2.74%), 7.06% (CI 5.89% to 8.38%) and 27.26% (CI 23.47% to 31.30%) in low-risk, intermediate-risk and high-risk groups (p value <0.001), containing 23%, 59% and 18% of subjects, respectively. In the validation set of 1475 subjects (AN prevalence of 8.4%), model performance was comparable (c-statistic=0.78), with AN risks of 2.73% (CI 1.25% to 5.11%), 5.57% (CI 4.12% to 7.34%) and 25.79% (CI 20.51% to 31.66%) in low-risk, intermediate-risk and high-risk subgroups, respectively (p<0.001), containing proportions of 23%, 59% and 18%. CONCLUSION: Among average-risk persons, this model estimates AN risk with high discrimination, identifying a lower risk subgroup that may be screened non-invasively and a higher risk subgroup for which colonoscopy may be preferred. The model could help guide patient-provider discussions of screening options, may increase screening adherence and conserve colonoscopy resources.

Mortality From Postscreening (Interval) Colorectal Cancers Is Comparable to That From Cancer in Unscreened Patients-A Randomized Sigmoidoscopy Trial.

BACKGROUND & AIMS: Endoscopic screening for colorectal cancer (CRC) is performed at longer time intervals than the fecal occult blood test or screenings for breast or prostate cancer. This causes concerns about interval cancers, which have been proposed to progress more rapidly. We compared outcomes of patients with interval CRCs after sigmoidoscopy screening vs outcomes of patients with CRC who had not been screened. METHODS: We performed a secondary analysis of a randomized sigmoidoscopy screening trial in Norway with 98,684 participants (age range, 50-64 years) who were randomly assigned to groups that were (n = 20,552) or were not (n = 78,126) invited for sigmoidoscopy screening from 1999 through 2001; participants were followed up for a median 14.8 years. We compared CRC mortality and all-cause mortality between individuals who underwent screening and were diagnosed with CRC 30 days or longer after screening (interval cancer group, n = 163) and individuals diagnosed with CRC in the nonscreened group (controls, n = 1740). All CRCs in the control group were identified when they developed symptoms (clinically detected CRCs). Analyses were stratified by cancer site. We used Cox regression to estimate hazard ratio (HRs), adjusted for age and sex. RESULTS: Over the follow-up period, 43 individuals in the interval cancer group died from CRC; among controls, 525 died from CRC. CRC mortality (adjusted HR, 0.98; 95% confidence interval, 0.72-1.35; P = .92), rectosigmoid cancer mortality (adjusted HR, 1.10; 95% confidence interval, 0.63-1.92; P = .74), and all-cause mortality (adjusted HR, 0.99; 95% confidence interval, 0.76-1.27; P = .91) did not differ significantly between the interval cancer group and controls. CONCLUSIONS: In this randomized sigmoidoscopy screening trial, mortality did not differ significantly between individuals with interval CRCs and unscreened patients with clinically detected CRCs. ClinicalTrials.gov identifier: NCT00119912.

Risk of Advanced Neoplasia Using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool.

Background: There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute's (NCI's) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons. Methods: This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy. We measured medical and family history, lifestyle information, and physical measures and calculated each person's future CRC risk using the NCI tool's logistic regression equation. We related quintiles of future CRC risk to the current risk of advanced neoplasia (sessile serrated polyp or tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or CRC). All statistical tests were two-sided. Results: For 4457 (98.5%) with complete data (mean age = 57.2 years, SD = 6.6 years, 51.7% women), advanced neoplasia prevalence was 8.26%. Based on quintiles of five-year estimated absolute CRC risk, current risks of advanced neoplasia were 2.1% (95% confidence interval [CI] = 1.3% to 3.3%), 4.8% (95% CI = 3.5% to 6.4%), 6.4% (95% CI = 4.9% to 8.2%), 10.0% (95% CI = 8.1% to 12.1%), and 17.6% (95% CI = 15.5% to 20.6%; P < .001). For quintiles of estimated 10-year CRC risk, corresponding current risks for advanced neoplasia were 2.2% (95% CI = 1.4% to 3.5%), 4.8% (95% CI = 3.5% to 6.4%), 6.5% (95% CI = 5.0% to 8.3%), 9.3% (95% CI = 7.5% to 11.4%), and 18.4% (95% CI = 15.9% to 21.1%; P < .001). Among persons with an estimated five-year CRC risk above the median, current risk for advanced neoplasia was 12.8%, compared with 3.7% among those below the median (relative risk = 3.4, 95 CI = 2.7 to 4.4). Conclusions: The NCI's Risk Assessment Tool, which estimates future CRC risk, may be used to estimate current risk for advanced neoplasia, making it potentially useful for tailoring and improving CRC screening efficiency among average-risk persons.

Institutional Responsibility and the Flawed Genomic Biomarkers at Duke University: A Missed Opportunity for Transparency and Accountability.

When there have been substantial failures by institutional leadership in their oversight responsibility to protect research integrity, the public should demand that these be recognized and addressed by the institution itself, or the funding bodies. This commentary discusses a case of research failures in developing genomic predictors for cancer risk assessment and treatment at a leading university. In its review of this case, the Office of Research Integrity, an agency within the US Department of Health and Human Services, focused their report entirely on one individual faculty member and made no comment on the institution's responsibility and its failure to provide adequate oversight and investigation. These actions missed an important opportunity to emphasize the institution's critical responsibilities in oversight of research integrity and the importance of institutional transparency and accountability.

Rationale and design of the European Polyp Surveillance (EPoS) trials.

BACKGROUND: Current guidelines recommend surveillance colonoscopies after polyp removal depending on the number and characteristics of polyps, but there is a lack of evidence supporting the recommendations. This report outlines the rationale and design of two randomized trials and one observational study investigating evidence-based surveillance strategies following polyp removal. Study design and endpoints: The EPoS studies started to recruit patients in April 2015. EPoS study I randomizes 13 746 patients with low-risk adenomas (1 - 2 tubular adenomas size < 10 mm, low-grade dysplasia) to surveillance after 5 and 10 years, or 10 years only. EPoS study II randomizes 13 704 patients with high-risk adenomas (3 - 10 adenomas or adenoma ≥ 10 mm in diameter, or adenoma with high-grade dysplasia, or > 25 % villous features) to surveillance after 3, 5, and 10 years, or 5 and 10 years only. EPoS study III offers surveillance after 5 and 10 years to patients with serrated polyps ≥ 10 mm in diameter at any location, or serrated polyps ≥ 5 mm in diameter proximal to the splenic flexure. All polyps are removed before patients enter the trials. The primary end point is colorectal cancer incidence after 10 years. We assume a colorectal cancer risk of 1 % for patients in EPoS I, and 2 % for patients in EPoS II. Using a noninferiority hypothesis with an equivalence interval of 0.5 % for EPoS I and 0.7 % for EPoS II, the trials are 90 % powered to uncover differences larger than the equivalence intervals. For EPoS III, no power analyses have been performed. CONCLUSIONS: The present trials aim to develop evidence-based strategies for polyp surveillance, thereby maximizing effectiveness and minimizing resources. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02319928).

Derivation and Validation of a Scoring System to Stratify Risk for Advanced Colorectal Neoplasia in Asymptomatic Adults: A Cross-sectional Study.

BACKGROUND: Several methods are recommended equally strongly for colorectal cancer screening in average-risk persons. Risk stratification would enable tailoring of screening within this group, with less invasive tests (sigmoidoscopy or occult blood tests) for lower-risk persons and colonoscopy for higher-risk persons. OBJECTIVE: To create a risk index for advanced neoplasia (colorectal cancer and adenomas or serrated polyps ≥1.0 cm, villous histology, or high-grade dysplasia) anywhere in the colorectum, using the most common risk factors for colorectal neoplasia. DESIGN: Cross-sectional study. SETTING: Multiple endoscopy units, primarily in the Midwest. PATIENTS: Persons aged 50 to 80 years undergoing initial screening colonoscopy (December 2004 to September 2011). MEASUREMENTS: Derivation and validation of a risk index based on points from regression coefficients for age, sex, waist circumference, cigarette smoking, and family history of colorectal cancer. RESULTS: Among 2993 persons in the derivation set, prevalence of advanced neoplasia was 9.4%. Risks for advanced neoplasia in persons at very low, low, intermediate, and high risk were 1.92% (95% CI, 0.63% to 4.43%), 4.88% (CI, 3.79% to 6.18%), 9.93% (CI, 8.09% to 12.0%), and 24.9% (CI, 21.1% to 29.1%), respectively (P < 0.001). Sigmoidoscopy to the descending colon in the low-risk groups would have detected 51 of 70 (73% [CI, 61% to 83%]) advanced neoplasms. Among 1467 persons in the validation set, corresponding risks for advanced neoplasia were 1.65% (CI, 0.20% to 5.84%), 3.31% (CI, 2.08% to 4.97%), 10.9% (CI, 8.26% to 14.1%), and 22.3% (CI, 16.9% to 28.5%), respectively (P < 0.001). Sigmoidoscopy would have detected 21 of 24 (87.5% [CI, 68% to 97%]) advanced neoplasms. LIMITATIONS: Split-sample validation; results apply to first-time screening. CONCLUSION: This index stratifies risk for advanced neoplasia among average-risk persons by identifying lower-risk groups for which noncolonoscopy strategies may be effective and efficient and a higher-risk group for which colonoscopy may be preferred. PRIMARY FUNDING SOURCE: National Cancer Institute, Walther Cancer Institute, Indiana University Simon Cancer Center, and Indiana Clinical and Translational Sciences Institute.

Leveraging biospecimen resources for discovery or validation of markers for early cancer detection.

Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well-conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers. With this background, the Division of Cancer Control and Population Sciences (DCCPS) and the Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) held a joint workshop in August 2013. The goal was to advance early detection cancer research by considering how the infrastructure of cohort studies that already exist or are being developed might be leveraged to include appropriate blood specimens, including prediagnostic specimens, ideally collected at periodic intervals, along with clinical data about symptom status and cancer diagnosis. Three overarching recommendations emerged from the discussions: 1) facilitate sharing of existing specimens and data, 2) encourage collaboration among scientists developing biomarkers and those conducting observational cohort studies or managing healthcare systems with cohorts followed over time, and 3) conduct pilot projects that identify and address key logistic and feasibility issues regarding how appropriate specimens and clinical data might be collected at reasonable effort and cost within existing or future cohorts.

Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): explanation and elaboration.

The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) Statement includes a 22-item checklist, which aims to improve the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD Statement is explained in detail and accompanied by published examples of good reporting. The document also provides a valuable reference of issues to consider when designing, conducting, and analyzing prediction model studies. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, it is recommended that authors include a completed checklist in their submission. The TRIPOD checklist can also be downloaded from www.tripod-statement.org.